3619Altitude Illness CHAPTER 462

Higher doses are not required. A meta-analysis limited to randomized

controlled trials revealed that 125 mg of acetazolamide twice daily was

effective in the prevention of AMS, with a relative-risk reduction of

~48% from values obtained with placebo. Even lower doses (62.5 mg

twice daily) have been reported to be effective. Paresthesia and a

tingling sensation are common side effects of acetazolamide. Some

other uncommon side effects are myopia and drowsiness. This drug

is a nonantibiotic sulfonamide that has low-level cross-reactivity with

sulfa antibiotics; as a result, severe reactions are rare. Dexamethasone

(8 mg/d in divided doses) is also effective. A large-scale, randomized,

double-blind, placebo-controlled trial in partially acclimatized trekkers

clearly showed that Ginkgo biloba is ineffective in the prevention of

AMS. In randomized studies, ibuprofen (600 mg three times daily) has

been shown to be beneficial in the prevention of AMS. Recently, acetaminophen (1 g three times daily) was as effective as ibuprofen at the

above dosage in a randomized, double-blind study, which did not have

a placebo arm. However, more definitive studies and (for ibuprofen) a

proper gastrointestinal bleeding risk assessment need to be conducted

before these drugs can be routinely recommended for AMS prevention.

Many drugs, including spironolactone, medroxyprogesterone, magnesium, calcium channel blockers, and antacids, confer no benefit in the

prevention of AMS. Starkly conflicting results from a number of trials

of inhaled budesonide for the prevention of AMS have recently been

published, but, in all likelihood, the drug is ineffective. Similarly, no

efficacy studies are available for coca leaves (a weak form of cocaine),

which are offered to high-altitude travelers in the Andes, or for soroche

pills, which contain aspirin, caffeine, and acetaminophen and are sold

over the counter in Bolivia and Peru. Finally, a word of caution applies

in the pharmacologic prevention of altitude illness. A fast-growing

population of climbers in pursuit of a summit are injudiciously using

prophylactic drugs such as glucocorticoids in an attempt to improve

their performance; the outcome can be tragic because of potentially

severe side effects of these drugs, especially if taken for a long duration.

For the treatment of mild AMS, rest alone with analgesic use may

be adequate. Descent and the use of acetazolamide and (if available)

oxygen are sufficient to treat most cases of moderate AMS. Even a minor

descent (400–500 m) may be adequate for symptom relief. For moderate

AMS or early HACE, dexamethasone (4 mg orally or parenterally) is

highly effective. For HACE, immediate descent is mandatory. When

descent is not possible because of poor weather conditions or darkness,

a simulation of descent in a portable hyperbaric chamber (Fig. 462-2)

can be very effective. Pressurization in the bag for 1–2 h often leads

to spectacular improvement and, like dexamethasone administration,

“buys time.” Thus, in certain high-altitude locations (e.g., remote

pilgrimage sites), the decision to bring along the lightweight hyperbaric

chamber may prove lifesaving. Like nifedipine, phosphodiesterase-5

inhibitors have no role in the treatment of AMS or HACE. Finally,

short-term oxygen inhalation using small cannisters of oxygen or by

visiting oxygen bars is unhelpful in the prevention of AMS.

■ HIGH-ALTITUDE PULMONARY EDEMA

Risk Factors and Manifestations Unlike HACE (a neurologic

disorder), HAPE is primarily a pulmonary problem and therefore is not

necessarily preceded by AMS. HAPE develops within 2–4 days after

arrival at high altitude; it rarely occurs after >4 or 5 days at the same

altitude, probably because of remodeling and adaptation that render

the pulmonary vasculature less susceptible to the effects of hypoxia.

A rapid rate of ascent, a history of HAPE, respiratory tract infections,

and cold environmental temperatures are risk factors. Men are more

susceptible than women. People with abnormalities of the cardiopulmonary circulation leading to pulmonary hypertension—e.g., mitral

stenosis, primary pulmonary hypertension, and unilateral absence

of the pulmonary artery—may be at increased risk of HAPE, even at

moderate altitudes. Although patent foramen ovale, a common condition, is four times more common among HAPE-susceptible individuals

than in the general population, there is no compelling evidence to

suggest causal effect. Echocardiography is recommended when HAPE

develops at relatively low altitudes (<3000 m) and whenever cardiopulmonary abnormalities predisposing to HAPE are suspected. The

differential diagnosis of HAPE includes anxiety attack, pneumonia,

pneumothorax, and pulmonary embolism.

The initial manifestation of HAPE may be a reduction in exercise

tolerance greater than that expected at the given altitude. Although a

dry, persistent cough may presage HAPE and may be followed by the

production of blood-tinged sputum, cough in the mountains is almost

universal and the mechanism is poorly understood. Tachypnea and

tachycardia, even at rest, are important markers as illness progresses.

Crackles may be heard on auscultation but are not diagnostic. HAPE

may be accompanied by signs of HACE. Patchy or localized opacities

(Fig. 462-3) or streaky interstitial edema may be noted on chest radiography. In the past, HAPE was mistaken for pneumonia due to the

cold or for heart failure due to hypoxia and exertion. Kerley B lines

or a bat-wing appearance are not seen on radiography. Electrocardiography may reveal right ventricular strain or even hypertrophy.

Hypoxemia and respiratory alkalosis are consistently present unless the

patient is taking acetazolamide, in which case metabolic acidosis may

supervene. Assessment of arterial blood gases is not necessary in the

evaluation of HAPE; an oxygen saturation reading with a pulse oximeter is generally adequate. The existence of a subclinical form of HAPE

has been suggested by an increased alveolar-arterial oxygen gradient

in Everest climbers near the summit, but hard evidence correlating

this abnormality with the development of clinically relevant HAPE is

FIGURE 462-2 A hyperbaric bag. The cylindrical, portable (<7 kg) nylon bag has

a one-way valve to prevent carbon dioxide buildup. A patient with severe acute

mountain sickness (AMS), high-altitude cerebral edema (HACE), or high-altitude

pulmonary edema (HAPE) is zipped inside the bag, which is continuously inflated

with a foot pedal. The increased barometric pressure (2 psi) inside the bag simulates

descent; for example, at 4250 m, the equivalent “elevation” inside the bag is ~2100 m.

No supplemental oxygen is required.

FIGURE 462-3 Chest radiograph of a patient with high-altitude pulmonary

edema shows opacity in the right middle and lower zones simulating pneumonic

consolidation. The opacity cleared almost completely in 2 days with descent and

supplemental oxygen.

3620 PART 15 Disorders Associated with Environmental Exposures

lacking. Comet-tail scoring—an ultrasound technique initially validated in cardiogenic pulmonary edema—has been used for evaluation

of extravascular lung water at high altitude and has proven to be useful

in detecting HAPE (clinical or subclinical) and even in ascertaining

whether the presence of extravascular lung water is a harbinger of

HAPE in patients with AMS.

Pathophysiology HAPE is a noncardiogenic pulmonary edema

with normal pulmonary artery wedge pressure. It is characterized by

patchy pulmonary hypoxic vasoconstriction that leads to overperfusion in some areas. This abnormality leads in turn to increased pulmonary capillary pressure (>18 mmHg) and capillary “stress” failure.

The exact mechanism for this hypoxic vasoconstriction is unknown.

Endothelial dysfunction due to hypoxia may play a role by impairing

the release of nitric oxide, an endothelium-derived vasodilator. At high

altitude, HAPE-prone persons have reduced levels of exhaled nitric

oxide. The effectiveness of phosphodiesterase-5 inhibitors in alleviating altitude-induced pulmonary hypertension, decreased exercise

tolerance, and hypoxemia supports the role of nitric oxide in the pathogenesis of HAPE. One study demonstrated that prophylactic use of

tadalafil, a phosphodiesterase-5 inhibitor, decreases the risk of HAPE

by 65%. In contrast, the endothelium also synthesizes endothelin-1, a

potent vasoconstrictor whose concentrations are higher than average

in HAPE-prone mountaineers.

Exercise and cold lead to increased pulmonary intravascular pressure

and may predispose to HAPE. In addition, hypoxia-triggered increases

in sympathetic drive may lead to pulmonary venoconstriction and

extravasation into the alveoli from the pulmonary capillaries. Consistent with this concept, phentolamine, which elicits α-adrenergic blockade, improves hemodynamics and oxygenation in HAPE more than do

other vasodilators. The study of tadalafil cited above also investigated

dexamethasone in the prevention of HAPE. Surprisingly, dexamethasone reduced the incidence of HAPE by 78%—a greater decrease than

with tadalafil. Besides possibly increasing the availability of endothelial

nitric oxide, dexamethasone may have altered the excessive sympathetic

activity associated with HAPE: the heart rate of participants in the dexamethasone arm of the study was significantly lowered. Finally, people

susceptible to HAPE also display enhanced sympathetic activity during

short-term hypoxic breathing at low altitudes.

Because many patients with HAPE have fever, peripheral leukocytosis, and an increased erythrocyte sedimentation rate, inflammation

has been considered an etiologic factor in HAPE. However, strong

evidence suggests that inflammation in HAPE is an epiphenomenon

rather than the primary cause. Nevertheless, inflammatory processes

(e.g., those elicited by viral respiratory tract infections) do predispose

persons to HAPE—even those who are constitutionally resistant to its

development.

Another proposed mechanism for HAPE is impaired transepithelial

clearance of sodium and water from the alveoli. β-Adrenergic agonists

upregulate the clearance of alveolar fluid in animal models. In a single

double-blind, randomized, placebo-controlled study of HAPE-susceptible

mountaineers, prophylactic inhalation of the β-adrenergic agonist salmeterol reduced the incidence of HAPE by 50%. However, the dosage

of salmeterol (125 μg twice daily) used was very high, which could

result in excessive tachycardia and tremors. Other effects of β agonists

may also contribute to the prevention of HAPE, and these findings are

in keeping with the concept that alveolar fluid clearance may play a

pathogenic role in this illness.

Prevention and Treatment (Table 462-1) Allowing sufficient

time for acclimatization by ascending gradually (as discussed above for

AMS and HACE) is the best way to prevent HAPE. Sustained-release

nifedipine (30 mg), given twice daily, prevents HAPE in people who

must ascend rapidly or who have a history of HAPE. Other drugs

for the prevention of HAPE are listed in Table 462-1 (footnote e).

Although dexamethasone is listed for prevention, its adverse effect

profile requires close monitoring. Acetazolamide has been shown to

blunt hypoxic pulmonary vasoconstriction in animal models, and this

observation warrants further study in HAPE prevention. However, one

large study failed to show a decrease in pulmonary vasoconstriction

in partially acclimatized individuals given acetazolamide. Inhaled

salmeterol is not recommended as clinical experience with this drug

is limited at high altitude. Finally, potent diuretics like furosemide

should be avoided in the treatment of HAPE. Early recognition is paramount in the treatment of HAPE, especially when it is not preceded

by the AMS symptoms of headache and nausea. Fatigue and dyspnea

at rest may be the only initial manifestations. Descent and the use of

supplementary oxygen (aimed at bringing oxygen saturation to >90%)

are the most effective therapeutic interventions. Exertion should be

kept to a minimum, and the patient should be kept warm. Hyperbaric

therapy (Fig. 462-2) in a portable altitude chamber may be lifesaving, especially if descent is not possible and oxygen is not available.

Oral sustained-release nifedipine (30 mg twice daily) can be used as

adjunctive therapy. No studies have investigated phosphodiesterase-5

inhibitors in the treatment of HAPE, but reports have described their

use in clinical practice. The mainstays of treatment remain descent and

(if available) oxygen.

In AMS, if symptoms abate (with or without acetazolamide), the

patient may reascend gradually to a higher altitude. Unlike that in acute

respiratory distress syndrome (another noncardiogenic pulmonary

edema), the architecture of the lung in HAPE is usually well preserved,

with rapid reversibility of abnormalities (Fig. 462-3). This fact has

allowed some people with HAPE to reascend slowly after a few days

of descent and rest. In HACE, reascent after a few days may not be

advisable during the same trip.

■ OTHER HIGH-ALTITUDE PROBLEMS

Sleep Impairment The mechanisms underlying sleep problems,

which are among the most common adverse reactions to high altitude,

include increased periodic breathing; changes in sleep architecture,

with increased time in lighter sleep stages; and changes in rapid eye

movement sleep. Sojourners should be reassured that sleep quality

improves with acclimatization. In cases where drugs do need to be

used, acetazolamide (125 mg before bedtime) is especially useful

because this agent decreases hypoxemic episodes and alleviates sleeping

disruptions caused by excessive periodic breathing. Whether combining acetazolamide with temazepam or zolpidem is more effective than

administering acetazolamide alone is unknown. In combinations, the

doses of temazepam and zolpidem should not be increased by >10 mg

at high altitudes. Limited evidence suggests that diazepam causes

hypoventilation at high altitudes and therefore is contraindicated. For

trekkers with obstructive sleep apnea who are using a continuous positive airway pressure (CPAP) machine, the addition of acetazolamide,

which will decrease centrally mediated sleep apnea, may be helpful.

There is evidence to show that obstructive sleep apnea at high altitude

may decrease and “convert” to central sleep apnea.

Gastrointestinal Issues High-altitude exposure may be associated with increased gastric and duodenal bleeding, but further studies

are required to determine whether there is a causal effect. Because of

decreased atmospheric pressure and consequent intestinal gas expansion at high altitudes, many sojourners experience abdominal bloating

and distension as well as excessive flatus expulsion. In the absence of

diarrhea, these phenomena are normal, if sometimes uncomfortable.

Accompanying diarrhea, however, may indicate the involvement of

bacteria or Giardia parasites, which are common at many high-altitude

locations in the developing world. Prompt treatment with fluids and

empirical antibiotics may be required to combat dehydration in the

mountains. Hemorrhoids are common on high-altitude treks; treatment includes hot soaks, application of hydrocortisone ointment, and

measures to avoid constipation.

High-Altitude Cough High-altitude cough can be debilitating

and is sometimes severe enough to cause rib fracture, especially at

>5000 m. The etiology of this common problem is probably multifactorial. Although high-altitude cough has been attributed to inspiration

of cold dry air, this explanation appears not to be sufficient by itself;

in long-duration studies in hypobaric chambers, cough has occurred

3621Altitude Illness CHAPTER 462

despite controlled temperature and humidity. The implication is that

hypoxia also plays a role. Exercise can precipitate cough at high altitudes, possibly because of water loss from the respiratory tract. In general, infection does not seem to be a common etiology. Many trekkers

find it useful to wear a balaclava to trap some moisture and heat. In

most situations, cough resolves upon descent.

High-Altitude Neurologic Events Unrelated to “Altitude

Illness” Transient ischemic attacks (TIAs) and strokes have been

well described in high-altitude sojourners outside the setting of altitude

sickness. However, these descriptions are not based on cause (hypoxia)

and effect. In general, symptoms of AMS present gradually, whereas

many of these neurologic events happen suddenly. The population that

suffers strokes and TIAs at sea level is generally an older age group with

other risk factors, whereas those so afflicted at high altitudes are generally younger and probably have fewer risk factors for atherosclerotic

vascular disease. Other mechanisms (e.g., migraine, vasospasm, focal

edema, hypocapneic vasoconstriction, hypoxia in the watershed zones

of minimal cerebral blood flow, or cardiac right-to-left shunt) may be

operative in TIAs and strokes at high altitude.

Subarachnoid hemorrhage, transient global amnesia, delirium,

and cranial nerve palsies (e.g., lateral rectus palsy) occurring at high

altitudes but outside the setting of altitude sickness have been well

described. Syncope is common at moderately high altitudes, generally occurs shortly after ascent, usually resolves without descent, and

appears to be a vasovagal event related to hypoxemia. Seizures occur

rarely with HACE, but hypoxemia and hypocapnia, which are prevalent

at high altitudes, are well-known triggers that may contribute to new

or breakthrough seizures in predisposed individuals. Nevertheless,

the consensus among experts is that sojourners with well-controlled

seizure disorders can ascend to high altitudes.

Finally, persons with hypercoagulable conditions (e.g., antiphospholipid syndrome, protein C deficiency) who are asymptomatic at

sea level may experience cerebral venous thrombosis (possibly due to

enhanced blood viscosity triggered by polycythemia and dehydration)

at high altitudes. Proper history taking, examination, and prompt

investigations where possible will help define these conditions as entities separate from altitude sickness. Administration of oxygen (where

available) and prompt descent are the cornerstones of treatment of

most of these neurologic conditions.

Ocular Problems Ocular issues are common in sojourners to high

altitudes. Hypoxemia induced by altitude leads to increased retinal

blood flow, which can be visible as engorged retinal veins on ophthalmoscopic examination. Both high flow and hypoxemic vascular damage causing permeability have been implicated in a breakdown of the

blood-retina barrier and the formation of retinal hemorrhages. Blot,

dot, flame, and white-centered hemorrhages can be observed. These

hemorrhages usually resolve spontaneously with descent, with only

mild symptoms and no lasting visual damage in most healthy eyes. The

exception is hemorrhage in the macular area. Macular hemorrhages

can cause devastating initial visual loss, particularly if bilateral, and

have been reported to cause permanently decreased vision in a few

cases.

Stroke syndromes such as retinal vein occlusion, retinal artery

occlusion, ischemic optic neuropathy, and cortical visual loss have

all been reported. With unilateral vision loss, it is always important

to check for a relative afferent pupillary defect. Increased hematocrit

combined with dehydration may contribute to these maladies. Glaucomatous optic nerve damage may progress with hypoxemia of altitude.

Acetazolamide is helpful both in combating the respiratory alkalosis

that comes with increased ventilation at high altitude and in lowering

the interocular pressure; its use should be considered in patients with

stable controlled glaucoma. Macular degeneration and diabetic eye

disease are not directly exacerbated by ascent to high altitude. Dry

eye and solar damage to the cornea, known as “snow blindness,” are

common. Wearing of high-quality UV-blocking sunglasses, even on

cloudy days, and attention to protecting and supplementing the tear

film with artificial tear drops can greatly improve comfort and vision.

Although modern refractive surgeries, such as photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK), are stable at high

altitude, patients who have undergone radial keratotomy should be

cautioned that hypoxemia to the cornea can lead to swelling that shifts

the refraction during ascent.

Psychological/Psychiatric Problems Delirium characterized

by a sudden change in mental status, a short attention span, disorganized thinking, and an agitated state during the period of confusion

has been well described in mountain climbers and trekkers without a

prior history. In addition, anxiety attacks, often triggered at night by

excessive periodic breathing, are well documented. The contribution

of hypoxia to these conditions is unknown. Expedition medical kits

need to include antipsychotic injectable drugs to control psychosis in

patients in remote high-altitude locations.

■ PREEXISTING MEDICAL ISSUES

Because travel to high altitudes is increasingly popular, common conditions such as hypertension, coronary artery disease, and diabetes are

more frequently encountered among high-altitude sojourners. This

situation is of particular concern for the millions of elderly pilgrims

with medical problems who visit high-altitude sacred areas (e.g., in the

Himalayas) each year. In recent years, high-altitude travel has attracted

intrepid trekkers who are taking immunosuppressive medications

(e.g., kidney transplant recipients or patients undergoing chemotherapy). Recommended vaccinations and other precautions (e.g., hand

washing) may be especially important for this group. Although most

of these medical conditions do not appear to influence susceptibility to

altitude illness, they may be exacerbated by ascent to altitude, exertion

in cold conditions, and hypoxemia. Advice regarding the advisability of

high-altitude travel and the impact of high-altitude hypoxia on these

preexisting conditions is becoming increasingly relevant, but there are

no evidence-based guidelines. In addition, recommendations made

for relatively low altitudes (~3000 m) may not hold true for higher

altitudes (>4000 m), where hypoxic stress is greater. Personal risks and

benefits must be clearly thought through before ascent.

Hypertension At high altitudes, enhanced sympathetic activity

may lead to a transient rise in blood pressure. Occasionally, nonhypertensive, healthy, asymptomatic trekkers have pathologically high blood

pressure at high altitude that rapidly normalizes without medicines

on descent. Sojourners should continue to take their antihypertensive

medications at high altitudes. Importantly, hypertensive patients are

not more likely than others to develop altitude illness. Because the

probable mechanism of high-altitude hypertension is α-adrenergic

activity, anti-α-adrenergic drugs such as prazosin have been suggested

for symptomatic patients and those with labile hypertension. It is best

to start taking the drug several weeks before the trip and to carry a

sphygmomanometer if a trekker has labile hypertension. Sustainedrelease nifedipine may also be useful. A recent observational cohort

study of 672 hypertensive and nonhypertensive trekkers in the

Himalayas showed that most travelers, including those with wellcontrolled hypertension, can be reassured that their blood pressure will

remain relatively stable at high altitude. Although blood pressure may

be extremely elevated at high altitude in normotensive and hypertensive people, it is unlikely to cause symptoms.

Coronary Artery Disease Myocardial oxygen demand and maximal heart rate are reduced at high altitudes because the VO2

 max

(maximal oxygen consumption) decreases with increasing altitude.

This effect may explain why signs of cardiac ischemia or dysfunction

usually are not seen in healthy persons at high altitudes. Asymptomatic, fit individuals with no risk factors need not undergo any tests for

coronary artery disease before ascent. For persons with ischemic heart

disease, previous myocardial infarction, angioplasty, and/or bypass

surgery, an exercise treadmill test is indicated. A strongly positive

treadmill test is a contraindication for high-altitude trips. Patients with

poorly controlled arrhythmias should avoid high-altitude travel, but

patients with arrhythmias that are well controlled with antiarrhythmic

medications do not seem to be at increased risk. Sudden cardiac deaths

3622 PART 15 Disorders Associated with Environmental Exposures

are not noted with a greater frequency in the Alps than at lower altitudes; although sudden cardiac deaths are encountered every trekking

season in the higher Himalayan range, accurate documentation is

lacking.

Cerebrovascular Disease Patients with TIAs should avoid travel

to high altitude for at least 3 months. Patients with known cerebral

aneurysm should also avoid high-altitude travel because of possible

rupture of the aneurysm due to increased cerebral blood flow at high

altitude.

Migraine Trekkers with a history of migraine may have an increased

likelihood of suffering from AMS and may also be predisposed to

headaches including altered character of their migraine presenting

with focal neurologic deficits. Oxygen inhalation may reduce AMStriggered headache, whereas a migraine headache usually persists even

after 10–15 min of oxygen inhalation.

Asthma Although cold air and exercise may provoke acute bronchoconstriction, asthmatic patients usually have fewer problems at

high than at low altitudes, possibly because of decreased allergen levels

and increased circulating catecholamine levels. Nevertheless, asthmatic

individuals should carry all their medications, including oral glucocorticoids, with proper instructions for use in case of an exacerbation.

Severely asthmatic persons should be cautioned against ascending to

high altitudes.

Pregnancy In general, low-risk pregnant women ascending to

3000 m are not at special risk except for the relative unavailability of

medical care in many high-altitude locations, especially in developing

countries. Despite the lack of firm data on this point, venturing higher

than 3000 m to altitudes at which oxygen saturation drops steeply

seems unadvisable for pregnant women.

Obesity Although living at a high altitude has been suggested as a

means of controlling obesity, obesity has also been reported to be a risk

factor for AMS, probably because nocturnal hypoxemia is more pronounced in obese individuals. Hypoxemia may also lead to greater pulmonary hypertension, thus possibly predisposing the trekker to HAPE.

Sickle Cell Disease High altitude is one of the rare environmental

exposures that occasionally provokes a crisis in persons with sickle

cell anemia. Even when traversing mountain passes as low as 2500 m,

people with sickle cell anemia have been known to have a vaso-occlusive

crisis. Patients with known sickle cell anemia who need to travel to

high altitudes should use supplemental oxygen and travel with caution.

Thalassemia has not been known to cause problems at high altitude.

Diabetes Mellitus Well-controlled diabetes is not a contraindication for travel to high altitude. Most of the high-altitude diabetes

advice is based on patients with type 1 diabetes and not type 2 diabetic

patients with comorbidities. An eye examination before travel may be

useful. Insulin pumps are increasingly used, but bubble formation in

the system may need to be closely monitored. Diabetic patients need

to carry a reliable glucometer. Ready access to sweets is also essential.

It is important for companions of diabetic trekkers to be fully aware of

potential problems like hypoglycemia. Dexamethasone, as far as possible, should be avoided in the prevention or treatment of altitude illness

in a diabetic patient.

Chronic Lung Disease Depending on disease severity and access

to medical care, preexisting lung disease may not always preclude

high-altitude travel. A proper pretravel evaluation must be conducted.

Supplemental oxygen may be required if the predicted PaO2

 for the altitude is <50–55 mmHg. Preexisting pulmonary hypertension may also

need to be assessed in these patients. If the result is positive, patients

should be discouraged from ascending to high altitudes; if such travel

is necessary, treatment with sustained-release nifedipine (20 mg twice a

day) should be considered. Small-scale studies have revealed that when

patients with bullous disease reach ~5000 m, bullous expansion and

pneumothorax are not noted. Compared with information on chronic

obstructive pulmonary disease, fewer data exist about the safety of

travel to high altitude for people with pulmonary fibrosis, but acute

exacerbation of pulmonary fibrosis has been seen at high altitude. A

handheld pulse oximeter can be useful to check for oxygen saturation.

Chronic Kidney Disease Patients with chronic kidney disease

can tolerate short-term stays at high altitudes, but theoretical concern

persists about progression to end-stage renal disease. Acetazolamide,

the drug most commonly used for altitude sickness, should be avoided

by anyone with preexisting metabolic acidosis, which can be exacerbated by this drug. In addition, the acetazolamide dosage should be

adjusted when the glomerular filtration rate falls to <50 mL/min, and

the drug should not be used at all if this value falls to <10 mL/min.

Cirrhosis Of patients with cirrhosis, 16% may have portopulmonary arterial hypertension, and 32% may have hepatopulmonary

syndrome; these conditions may be detrimental at high altitude as they

may cause exaggerated hypoxemia. Thus, screening for these problems

is important in cirrhotic patients planning a high-altitude trip. In addition, acetazolamide may be inadvisable in these patients as the drug

may increase the risk of hepatic encephalopathy.

Dental Problems Air resulting from decay in the root system

could expand on ascent and lead to increasing pain. A good dental

checkup before a trekking or climbing trip may be prudent.

■ CHRONIC MOUNTAIN SICKNESS AND HIGHALTITUDE PULMONARY HYPERTENSION IN

HIGHLANDERS

The largest populations of highlanders live in the South American

Andes, the Tibetan Plateau, and parts of Ethiopia. Chronic mountain

sickness (Monge’s disease) is a disease in highlanders that is characterized by excessive erythrocytosis with moderate to severe pulmonary

hypertension leading to cor pulmonale. This condition was originally described in South America and has also been documented in

Colorado and in the Han Chinese population in Tibet; it is much less

common in Tibetans or in Ethiopian highlanders. Migration to a low

altitude results in the resolution of chronic mountain illness. Venesection and acetazolamide are helpful.

High-altitude pulmonary hypertension is also a subacute disease

of long-term high-altitude residents. Unlike Monge’s disease, this

syndrome is characterized primarily by pulmonary hypertension

(not erythrocytosis) leading to heart failure. Indian soldiers living at

extreme altitudes for prolonged periods and Han Chinese infants born

in Tibet have presented with the adult and infantile forms, respectively.

High-altitude pulmonary hypertension bears a striking pathophysiologic resemblance to brisket disease in cattle. Descent to a lower

altitude is curative.

■ FURTHER READING

Basnyat B: High altitude pilgrimage medicine. High Alt Med Biol

15:434, 2014.

Basnyat B, Murdoch D: High altitude illness. Lancet 361:1967, 2003.

Hillebrandt D et al: UIAA medical commission recommendations

for mountaineers, hillwalkers, trekkers, and rock and ice climbers

with diabetes. High Alt Med Biol, 2018. [Epub ahead of print]

Keyes LE et al: Blood pressure and altitude: An observational cohort

study of hypertensive and nonhypertensive Himalayan trekkers in

Nepal. High Alt Med Biol 18:267, 2017.

Luks AM et al: Wilderness Medical Society practice guidelines for

the prevention and treatment of acute altitude illness: 2019 update.

Wilderness Environ Med 30:S3, 2019.

Mcintosh SE et al: Reduced acetazolamide dosing in countering altitude illness: A comparison of 62.5 vs 125 mg (the RADICAL Trial).

Wilderness Environ Med 30:12, 2019.

Roach RC et al: Mountain medicine, in Wilderness Medicine, 7th ed.

PS Auerbach et al (eds). Philadelphia, Elsevier, 2017, pp 2–39.

3623Hyperbaric and Diving Medicine CHAPTER 463

WHAT IS HYPERBARIC

AND DIVING MEDICINE?

Hyperbaric medicine is the treatment of health disorders using wholebody exposure to pressures >101.3 kPa (1 atmosphere or 760 mmHg).

In practice, this almost always means the administration of hyperbaric

oxygen therapy (HBO2

T). The Undersea and Hyperbaric Medical

Society (UHMS) defines HBO2

T as: “an intervention in which an

individual breathes near 100% oxygen intermittently while inside

a hyperbaric chamber that is pressurized to greater than sea level

pressure (1 atmosphere absolute, or ATA). For clinical purposes, the

pressure must equal or exceed 1.4 ATA.” The chamber is an airtight

vessel variously called a hyperbaric chamber, recompression chamber,

or decompression chamber, depending on the clinical and historical

context. Such chambers may be capable of compressing a single patient

(a monoplace chamber) or multiple patients and attendants as required

(a multiplace chamber) (Figs. 463-1 and 463-2). Historically, these

compression chambers were first used for the treatment of divers and

compressed air workers suffering decompression sickness (DCS; “the

bends”). Although the prevention and treatment of disorders arising

after decompression in diving, aviation, and space flight have developed into a specialized field of their own, they remain closely linked to

the broader practice of hyperbaric medicine.

Despite an increased understanding of mechanisms and an improving evidence basis, hyperbaric medicine has struggled to achieve

widespread recognition as a “legitimate” therapeutic measure. There

are several contributing factors, but high among them are a poor

grounding in general oxygen physiology and oxygen therapy at medical

schools and a continuing tradition of charlatans advocating hyperbaric

therapy (often using air) as a panacea. Funding for both basic and clinical research has been difficult in an environment where the pharmacologic agent under study is abundant, cheap, and unpatentable. There

are signs of an improved appreciation of the potential importance of

HBO2

T with significant National Institutes of Health (NIH) funding

for mechanisms research, from the U.S. military for clinical investigation, and as evidenced by the recent appreciation of HBO2

T as a

potentially useful tool for improving oxygenation in severe COVID-19

(see “Further Readings”).

MECHANISMS OF HYPERBARIC OXYGEN

Increased hydrostatic pressure will reduce the volume of any bubbles present within the body (see “Diving Medicine”), and this is

partly responsible for the success of prompt recompression in DCS

and arterial gas embolism. Supplemental oxygen breathing has a

463

dose-dependent effect on oxygen transport, ranging from improvement in hemoglobin oxygen saturation when a few liters per minute

are delivered by simple mask at 101.3 kPa (1 ATA) to raising the dissolved plasma oxygen sufficiently to sustain life without the need for

hemoglobin at all when 100% oxygen is breathed at 303.9 kPa (3 ATA).

Most HBO2

T regimens involve oxygen breathing at between 202.6 and

283.6 kPa (2 and 2.8 ATA), and the resultant increase in arterial oxygen

tensions to >133.3 kPa (1000 mmHg) has widespread physiologic and

pharmacologic consequences (Fig. 463-3).

One direct consequence of such high intravascular tension is to

increase greatly the effective capillary-tissue diffusion distance for

oxygen such that oxygen-dependent cellular processes can resume in

hypoxic tissues. Important as this may be, the mechanism of action is

not limited to this restoration of oxygenation in hypoxic tissue. Indeed,

there are pharmacologic effects that are profound and long-lasting.

Although removal from the hyperbaric chamber results in a rapid

return of poorly vascularized tissues to their hypoxic state, even a

single dose of HBO2

T produces changes in fibroblast, leukocyte and

angiogenic functions, and antioxidant defenses that persist many hours

after oxygen tensions are returned to pretreatment levels.

It is widely accepted that oxygen in high doses produces adverse

effects due to the production of reactive oxygen species (ROS) such as

superoxide (O2

–

) and hydrogen peroxide (H2

O2

). It has become increasingly clear over the past decade that both ROS and reactive nitrogen species (RNS) such as nitric oxide (NO) participate in diverse intracellular

signaling pathways involved in the production of a range of cytokines,

growth factors, and other inflammatory and repair modulators. Such

mechanisms are complex and at times apparently paradoxical. For

example, when used to treat chronic hypoxic wounds, HBO2

T has been

shown to enhance the clearance of cellular debris and bacteria by providing the substrate for macrophage phagocytosis; stimulate growth factor

synthesis by increased production and stabilization of hypoxia-inducible

factor 1 (HIF-1); inhibit leukocyte activation and adherence to damaged

endothelium; and mobilize CD34+ pluripotent vasculogenic progenitor

cells from the bone marrow. The interactions between these mechanisms

remain a very active field of investigation. One exciting development

is the concept of hyperoxic preconditioning in which a short exposure

to HBO2

 can induce tissue protection against future hypoxic/ischemic

insult, most likely through an inhibition of mitochondrial permeability

transition pore (MPTP) opening and the release of cytochrome c. By

targeting these mechanisms of cell death during reperfusion events,

HBO2

 has potential applications in a variety of settings including organ

transplantation. One randomized clinical trial suggested that HBO2

T

prior to coronary artery bypass grafting reduces biochemical markers of

ischemic stress and improves neurocognitive outcomes.

ADVERSE EFFECTS OF THERAPY

HBO2

T is generally well tolerated and safe in clinical practice. About

17% of patients experience an adverse event at some time during their

treatment course, and most are mild and self-limiting. Adverse effects

Hyperbaric and Diving

Medicine

Michael H. Bennett, Simon J. Mitchell

FIGURE 463-1 A monoplace chamber. (Prince of Wales Hospital, Sydney.)

FIGURE 463-2 A chamber designed to treat multiple patients. (Karolinska University

Hospital.)

3624 PART 15 Disorders Associated with Environmental Exposures

are associated with both alterations in pressure (barotrauma) and the

administration of oxygen.

■ BAROTRAUMA

Barotrauma occurs when any noncompliant gas-filled space within

the body does not equalize with environmental pressure during compression or decompression. About 10% of patients complain of some

difficulty equalizing middle-ear pressure early in compression, and

although most of these problems are minor and can be overcome with

training, 2–5% of conscious patients require middle-ear ventilation

tubes or formal grommets across the tympanic membrane. Unconscious patients cannot equalize and should have middle-ear ventilation

tubes placed prior to compression if possible. Other less common sites

for barotrauma of compression include the respiratory sinuses and

dental caries. The lungs are potentially vulnerable to barotrauma of

decompression as described below in the section on diving medicine,

but the decompression following HBO2

T is so slow that pulmonary gas

trapping is extremely rare in the absence of an undrained pneumothorax or lesions such as bullae.

■ OXYGEN TOXICITY

The practical limit to the dose of oxygen, either in a single treatment

session or in a series of daily sessions, is oxygen toxicity. The most

common acute manifestation is a seizure, often preceded by anxiety

and agitation, during which time a switch from oxygen to air breathing

may avoid the convulsion. Hyperoxic seizures are typically generalized

tonic-clonic seizures followed by a variable postictal period. The cause

is an overwhelming of the antioxidant defense systems within the

brain. Although clearly dose-dependent, onset is very variable both

between individuals and within the same individual on different days.

In routine clinical hyperbaric practice, the incidence is ~1:1500 to

1:3000 compressions.

Chronic oxygen poisoning most commonly manifests as myopic

shift. This is due to alterations in the refractive index of the lens

following oxidative damage that reduces the solubility of lenticular

proteins in a process similar to that associated with senescent cataract

formation. Up to 75% of patients show deterioration in visual acuity

after a course of 30 treatments at 202.6 kPa (2 ATA). Although most

return to pretreatment values 6–12 weeks after cessation of treatment, a

small proportion do not recover. A more rapid maturation of preexisting cataracts has occasionally been associated with HBO2

T. Although

a theoretical problem, the development of pulmonary oxygen toxicity

over time does not seem to be problematic in practice—probably due

to the intermittent nature of the exposure.

CONTRAINDICATIONS TO

HYPERBARIC OXYGEN

There are few absolute contraindications to HBO2

T. The most commonly encountered is an untreated pneumothorax. A pneumothorax

may expand rapidly on decompression and come under tension. Prior

to any compression, patients with a pneumothorax should have a patent chest drain in place. The presence of other obvious risk factors for

pulmonary gas trapping such as bullae should trigger a very cautious

analysis of the risks of treatment versus benefit. Prior bleomycin treatment deserves special mention because of its association with a partially

dose-dependent pneumonitis in ~20% of people. These individuals

appear to be at particular risk for rapid deterioration of ventilatory

function following exposure to high oxygen tensions. The relationship

between distant bleomycin exposure and subsequent risk of pulmonary oxygen toxicity is uncertain; however, late pulmonary fibrosis is a

potential complication of bleomycin, and any patient with a history of

receiving this drug should be carefully counseled prior to exposure to

HBO2

T. For those recently exposed to doses >300,000 IU (200 mg) and

whose course was complicated by a respiratory reaction to bleomycin,

compression should be avoided except in a life-threatening situation.

INDICATIONS FOR HYPERBARIC OXYGEN

The appropriate indications for HBO2

T are controversial and evolving. Practitioners in this area are in an unusual position. Unlike most

branches of medicine, hyperbaric physicians do not deal with a range

of disorders within a defined organ system, nor are they masters

of a therapy specifically designed for a single category of disorders.

Hyperbaric oxygen

Restoration of

tissue normoxia

Edema

reduction

Hyperoxic

vasoconstriction

↑Wound growth

factors

Stem cell

mobilization

↓β2 integrin

function

Enhanced phagocytosis,

angiogenesis, and

fibroblast activity

Ischemic

preconditioning,

e.g., HIF-1 HO-1

Wound healing,

radiation tissue injury

Threatened grafts/flaps

cadaveric organ preservation

Enhanced inert gas

diffusion gradients between

bubble, tissue, and lungs

High

arterial PO2

Hydrostatic

compression

Bubble

volume

reduction

DCS

CAGE

Enhanced O2 diffusion Osmotic effect Generation of ROS and RNS

Crush injury

FIGURE 463-3 Mechanisms of action of hyperbaric oxygen. There are many consequences of compression and oxygen breathing. The cell-signaling effects of hyperbaric

oxygen therapy (HBO2

T) are the least understood but potentially most important. Examples of indications for use are shown in the shaded boxes. CAGE, cerebral arterial

gas embolism; DCS, decompression sickness; HIF-1, hypoxia-inducible factor-1; HO-1, hemoxygenase 1; RNS, reactive nitrogen species; ROS, reactive oxygen species.

3625Hyperbaric and Diving Medicine CHAPTER 463

Inevitably, the encroachment of hyperbaric physicians into other

medical fields generates suspicion from specialist practitioners in

those fields. At the same time, this relatively benign therapy, the prescription and delivery of which requires no medical license in most

jurisdictions (including the United States), attracts both charlatans

and well-motivated proselytizers who tout the benefits of oxygen for

a plethora of chronic incurable diseases. This battle on two fronts has

meant that mainstream hyperbaric physicians have been particularly

careful to claim effectiveness only for those conditions where there is a

reasonable body of supporting evidence.

In 1977, the UHMS systematically examined claims for the use of

HBO2

T in >100 disorders and found sufficient evidence to support

routine use in only 12. The Hyperbaric Oxygen Therapy Committee

of that organization has continued to update this list periodically with

an increasingly formalized system of appraisal for new indications and

emerging evidence (Table 463-1). Around the world, other relevant

medical organizations have generally taken a similar approach. Indications vary considerably across the globe—particularly those recommended by hyperbaric medical societies in Russia and China where

HBO2

T has gained much wider support than in the United States,

Europe, and Australasia. Nevertheless, there are now 31 Cochrane

reviews summarizing the randomized trial evidence for 27 putative

indications, including attempts to examine the cost-effectiveness of

HBO2

T. Table 463-2 is a synthesis of these two approaches and lists

the estimated cost of attaining health outcomes with the use of HBO2

T.

Any savings associated with alternative treatment strategies avoided as

a result of HBO2

T are not accounted for in these estimates (e.g., the

avoidance of lower leg amputation in diabetic foot ulcers). Following

are short reviews of three important indications currently accepted by

the UHMS.

■ LATE RADIATION TISSUE INJURY

Radiotherapy is a well-established treatment for suitable malignancies. In the United States alone, ~300,000 individuals annually will

become long-term survivors of cancer treated by irradiation. Serious

radiation-related complications developing months or years after

treatment (late radiation tissue injury [LRTI]) will significantly affect

between 5 and 15% of those long-term survivors, although incidence

varies widely with dose, age, and site. LRTI is most common in the

head and neck, chest wall, breast, and pelvis.

Pathology and Clinical Course With time, tissues undergo a

progressive deterioration characterized by a reduction in the density

of small blood vessels (reduced vascularity) and the replacement

of normal tissue with dense fibrous tissue (fibrosis). An alternative

model of pathogenesis suggests that rather than a primary hypoxia, the

principal trigger is an overexpression of inflammatory cytokines that

promote fibrosis, probably through oxidative stress and mitochondrial

dysfunction, and a secondary tissue hypoxia. Ultimately, and often

triggered by a further physical insult such as surgery or infection, there

may be insufficient oxygen to sustain normal function, and the tissue

becomes necrotic (radiation necrosis). LRTI may be life-threatening

and significantly reduce quality of life. Historically, the management of

these injuries has been unsatisfactory. Conservative treatment is usually restricted to symptom management, whereas definitive treatment

traditionally entails surgery to remove the affected part and extensive

repair. Surgical intervention in an irradiated field is often disfiguring

and associated with an increased incidence of delayed healing, breakdown of a surgical wound, or infection. HBO2

T may act by several

mechanisms to improve this situation, including edema reduction,

vasculogenesis, and enhancement of macrophage activity (Fig. 463-3).

The intermittent application of HBO2

 is the only intervention shown to

increase the microvascular density in irradiated tissue.

Clinical Evidence The typical course of HBO2

T consists of 30

once-daily compressions to 202.6–243.1 kPa (2–2.4 ATA) for 1.5–2 h

each session, often bracketed around surgical intervention if required.

Although HBO2

T has been used for LRTI since at least 1975, most

clinical studies have been limited to small case series or individual

case reports. In a review, Feldmeier and Hampson located 71 such

reports involving a total of 1193 patients across eight different tissues.

There were clinically significant improvements in the majority of

patients, and only 7 of 71 reports indicated a generally poor response

to HBO2

T. A Cochrane systematic review with meta-analysis included

14 randomized trials published since 1985 and drew the following

conclusions (see Table 463-2 for numbers needed to treat): HBO2

T

improves healing in radiation proctitis (relative risk [RR] of healing

with HBO2

T, 1.72; 95% confidence interval [CI], 1.0–2.9) and achievement of mucosal cover of bone after hemimandibulectomy and reconstruction of the mandible (RR, 1. 3; 95% CI, 1.1–1.6); HBO2

T prevents

the development of osteoradionecrosis following tooth extraction from

a radiation field (RR, 1.4; 95% CI, 1.08–1.7) and reduces the risk of

wound dehiscence following grafts and flaps in the head and neck (RR,

4.2; 95% CI, 1.1–16.8). Conversely, there was no evidence of benefit in

established radiation brachial plexus lesions or brain injury.

■ SELECTED PROBLEM WOUNDS

A problem wound is any cutaneous ulceration that requires a prolonged time to heal, does not heal, or recurs. In general, wounds

referred to hyperbaric facilities are those where sustained attempts to

heal by other means have failed. Problem wounds are common and

constitute a significant health problem. It has been estimated that 1%

of the population of industrialized countries will experience a leg ulcer

at some time. The global cost of chronic wound care may be as high as

U.S. $25 billion per year.

Pathology and Clinical Course By definition, chronic wounds

are indolent or progressive and resistant to the wide array of treatments applied. Although there are many contributing factors, most

commonly, these wounds arise in association with one or more comorbidities such as diabetes, peripheral venous or arterial disease, or prolonged pressure (decubitus ulcers). First-line treatments are aimed at

correction of the underlying pathology (e.g., vascular reconstruction,

compression bandaging, or normalization of blood glucose level), and

HBO2

T is an adjunctive therapy to good general wound care practice

to maximize the chance of healing.

For most indolent wounds, hypoxia is a major contributor to failure

to heal. Many guidelines to patient selection for HBO2

T include the

interpretation of transcutaneous oxygen tensions around the wound

while breathing air and oxygen at pressure (Fig. 463-4). Wound healing is a complex and incompletely understood process. While it appears

that in acute wounds healing is stimulated by the initial hypoxia, low

pH, and high lactate concentrations found in freshly injured tissue,

some elements of tissue repair are extremely oxygen dependent, for

example, collagen elaboration and deposition by fibroblasts and bacterial killing by macrophages. In this complicated interaction between

TABLE 463-1 Current List of Indications for Hyperbaric Oxygen

Therapy

1. Air or gas embolism (includes diving-related, iatrogenic, and accidental

causes)

2. Carbon monoxide poisoning (including poisoning complicated by cyanide

poisoning)

3. Clostridial myositis and myonecrosis (gas gangrene)

4. Crush injury, compartment syndrome, and acute traumatic ischemias

5. Decompression sickness

6. Arterial insufficiency including central retinal arterial occlusion and problem

wounds

7. Severe anemia

8. Intracranial abscess

9. Necrotizing soft tissue infections (e.g., Fournier’s gangrene)

10. Osteomyelitis (refractory to other therapy)

11. Delayed radiation injury (soft-tissue injury and bony necrosis)

12. Skin grafts and flaps (compromised)

13. Acute thermal burn injury

14. Sudden sensorineural hearing loss

Source: The Undersea and Hyperbaric Medical Society (2021).

3626 PART 15 Disorders Associated with Environmental Exposures

TABLE 463-2 Selected Indications for Which There Is Promising Efficacy for the Application of Hyperbaric Oxygen Therapy

DIAGNOSIS

OUTCOME (NUMBER OF

SESSIONS) NNT AND 95% CI

ESTIMATED COST TO PRODUCE

ONE EXTRA FAVORABLE

OUTCOME AND 95% CI (USD) COMMENTS AND RECOMMENDATIONS

Radiation tissue injury More information is required on the subset of disease severity, the affected tissue type that is most likely to benefit, and the time over

which benefit may persist.

Resolved proctitis (30) 3 22,392 Large ongoing multicenter trial

2–11 14,928–82,104

Healed mandible (30) 4 29,184 Based on one poorly reported study

2–8 14,592–58,368

Mucosal cover in ORN (30) 3 29,888 Based on one poorly reported study

2–4 14,592–29,184

Bony continuity in ORN (30) 4 29,184 Based on one poorly reported study

2–8 14,592–58,368

Prevention of ORN after dental

extraction (30)

4 29,184 Based on a single study

2–13 14,592–94,848

Prevention of dehiscence (30) 5 36,480 Based on one poorly reported study

3–8 21,888–58,368

Chronic wounds More information is required on the subset of disease severity or classification most likely to benefit, the time over which benefit may

persist, and the most appropriate oxygen dose. Economic analysis is required.

Diabetic ulcer healed at

1 year (30)

2 14,928 Based on one small study, more research

required

1–5 7464–37,320

Diabetic ulcer, major

amputation avoided (30)

4 29,856 Three small studies; outcome over a

longer time period required

3–11 22,392–82,104

ISSNHL No evidence of benefit >2 weeks after onset. More research is required to define the role (if any) of HBO2

T in routine therapy.

Improvement of 25% in hearing

loss within 2 weeks of onset

(15)

5 18,240 Some improvement in hearing, but

functional significance unknown

3–20 10,944–72,960

Acute coronary syndrome More information is required on the subset of disease severity and timing of therapy most likely to result in benefit. Given the potential

of HBO2

T in modifying ischemia-reperfusion injury, attention should be given to the combination of HBO2

T and thrombolysis in early

management and in the prevention of restenosis after stent placement.

Episode of MACE (5) 4 4864 Based on a single small study; more

research required

3–10 3648–12,160

Incidence of significant

dysrhythmia (5)

6 7296 Based on a single moderately powered

study in the 1970s

3–24 3648–29,184

Traumatic brain injury Limited evidence that for acute injury HBO2

T reduces mortality but not functional morbidity. Routine use not yet justified.

Mortality (15) 7 34,104 Based on four heterogeneous studies

4–22 19,488–58,464

Enhancement of

radiotherapy

There is some evidence that HBO2

T improves local tumor control, reduces mortality for cancers of the head and neck, and reduces the

chance of local tumor recurrence in cancers of the head, neck, and uterine cervix.

Head and neck cancer: 5-year

mortality (12)

5 14,592 Based on trials performed in the 1970s and

1980s. There may be some confounding by

radiation fractionation schedule.

3–14 8755–40,858

Local recurrence 1 year (12) 5 14,592 May no longer be relevant to therapy

4–8 11,674–23,347

Cancer of uterine cervix: Local

recurrence at 2 years (20)

5 24,320 As above

4–8 19,456–38,912

Decompression illnessa Reasonable evidence for reduced number of HBO2

T sessions but similar outcomes when NSAID added.

Reduction of HBO2

T treatment

requirement by 1

5

3–18

N/R Single appropriately powered randomized

trial

a

Tenoxicam used as an adjunct to recompression on oxygen.

Abbreviations: CI, confidence interval; HBO2

T, hyperbaric oxygen therapy; ISSNHL, idiopathic sudden sensorineural hearing loss; MACE, major adverse cardiac events; NNT,

number needed to treat; N/R, not remarkable; NSAID, nonsteroidal anti-inflammatory drug; ORN, osteoradionecrosis; USD, U.S. dollars.

Source: M Bennett: The evidence-basis of diving and hyperbaric medicine—a synthesis of the high level evidence with meta-analysis. http://unsworks.unsw.edu.au/fapi/

datastream/unsworks:949/SOURCE01?view=true.

3627Hyperbaric and Diving Medicine CHAPTER 463

Transcutaneous

wound mapping on air

Transcutaneous mapping

on 100% oxygen 1 ATA

HBO2T unlikely to be

effective

Problem wound

referred for assessment

Suitable for

compression?

Contraindication, critical

major vessel disease, or

surgical option available

HBO2T indicated on

a case-by-case basis.

Consider alternatives.

PtcO2 35–100 mmHg

PtcO2 >100 mmHg

PtcO2 >200 mmHg

Transcutaneous mapping

on 100% oxygen 2.4 ATA HBO2T indicated

No

Yes

Not hypoxic

(PtcO2 >40 mmHg)

PtcO2 >100 but

<200 mmHg

PtcO2 <100 mmHg

PtcO2 <35 mmHg

unresponsive

PtcO2 <40 mmHg*

One schema for using

transcutaneous oximetry

to assist in patient

selection for HBO2T.

If the wound area is

hypoxic and responds to

the administration of

oxygen at 1 ATA or 2.4 ATA,

treatment may be justified.

FIGURE 463-4 Determining suitability for hyperbaric oxygen therapy (HBO2

T) guided by transcutaneous oximetry around the wound bed. *In diabetic patients, <50 mmHg

may be more appropriate. PtcO2

, transcutaneous oxygen pressure.

wound hypoxia and periwound oxygenation, successful healing relies

on adequate tissue oxygenation in the area surrounding the fresh

wound. Certainly, wounds that lie in hypoxic tissue beds are those

that most often display poor or absent healing. Some causes of tissue

hypoxia will be reversible with HBO2

T, whereas some will not (e.g., in

the presence of severe large vessel disease). When tissue hypoxia can

be overcome by a high driving pressure of oxygen in the arterial blood,

this can be demonstrated by measuring the tissue partial pressure of

oxygen using an implantable oxygen electrode or, more commonly, a

modified transcutaneous Clarke electrode.

The intermittent presentation of oxygen to those hypoxic tissues

facilitates a resumption of healing. These short exposures to high

oxygen tensions have long-lasting effects (at least 24 h) on a wide range

of healing processes (Fig. 463-3). The result is a gradual improvement

in oxygen tension around the wound that reaches a plateau in experimental studies at ~20 treatments over 4 weeks. Improvements in oxygenation are associated with an eight- to ninefold increase in vascular

density over both normobaric oxygen and air-breathing controls.

Clinical Evidence The typical course of HBO2

T consists of 20–30

once-daily compressions to 2–2.4 ATA for 1.5–2 h each session but is

highly dependent on the clinical response. There are many case series

in the literature supporting the use of HBO2

T for a wide range of problem wounds. Both retrospective and prospective cohort studies suggest

that 6 months after a course of therapy, ~70% of indolent ulcers will be

substantially improved or healed. Often these ulcers have been present

for many months or years, suggesting the application of HBO2

T has a

profound effect, either primarily or as a facilitator of other strategies.

A recent Cochrane review included 12 randomized controlled trials

(RCTs) and concluded that the chance of a diabetic ulcer healing

improved with HBO2

T (10 trials; RR, 2.35; 95% CI, 1.19–4.62; p = .01).

Although there was a trend to benefit with HBO2

T, there was no statistically significant difference in the rate of major amputations (RR, 0.36;

95% CI, 0.11–1.18).

■ CARBON MONOXIDE POISONING

Carbon monoxide (CO) is a colorless, odorless gas formed during

incomplete hydrocarbon combustion. Although CO is an essential

endogenous neurotransmitter linked to NO metabolism and activity,

it is also a leading cause of poisoning death and, in the United States

alone, results in >50,000 emergency department visits per year and

~2000 deaths. Although there are large variations from country to

country, about half of nonlethal exposures are due to self-harm. Accidental poisoning is commonly associated with defective or improperly

installed heaters, house fires, and industrial exposures. The motor

vehicle is by far the most common source of intentional poisoning.

Pathology and Clinical Course The pathophysiology of CO

exposure is incompletely understood. CO binds to hemoglobin with

an affinity >200 times that of oxygen, directly reducing the oxygencarrying capacity of blood and further promoting tissue hypoxia by

shifting the oxyhemoglobin dissociation curve to the left. CO is also

an anesthetic agent that inhibits evoked responses and narcotizes

experimental animals in a dose-dependent manner. The associated

loss of airway patency together with reduced oxygen carriage in blood

may cause death from acute arterial hypoxia in severe poisoning. CO

may also cause harm by other mechanisms including direct disruption

of cellular oxidative processes, binding to myoglobin and hepatic cytochromes, and peroxidation of brain lipids.

The brain and heart are the most sensitive target organs due to

their high blood flow, poor tolerance of hypoxia, and high oxygen

requirements. Minor exposure may be asymptomatic or present with

vague constitutional symptoms such as headache, lethargy, and nausea,

whereas higher doses may present with poor concentration and cognition, short-term memory loss, confusion, seizures, and loss of consciousness. While carboxyhemoglobin (COHb) levels on admission do

not necessarily reflect the severity or the prognosis of CO poisoning,

cardiorespiratory arrest carries a very poor prognosis. Over the longer

term, surviving patients commonly have neuropsychological sequelae.

Motor disturbances, peripheral neuropathy, hearing loss, vestibular

abnormalities, dementia, and psychosis have all been reported. Risk

factors for poor outcome are age >35 years, exposure for >24 h, acidosis, and loss of consciousness.

Clinical Evidence The typical course of HBO2

T consists of two

to three compressions to 2–2.8 ATA for 1.5–2 h each session. It is

common for the first two compressions to be delivered within 24 h of

the exposure. CO poisoning is one of the longest-standing indications

for HBO2

T—based largely on the obvious connection between exposure, tissue hypoxia, and the ability of HBO2

T to rapidly overcome

this hypoxia. CO is eliminated rapidly via the lungs on application of

HBO2

T, with a half-life of ~21 min at 2.0 ATA versus 5.5 h breathing

air and 71 min breathing oxygen at sea level. In practice, however, it

seems unlikely that HBO2

T can be delivered in time to prevent either

3628 PART 15 Disorders Associated with Environmental Exposures

acute hypoxic death or irreversible global cerebral hypoxic injury. If

HBO2

T is beneficial in CO poisoning, it must reduce the likelihood of

persisting and/or delayed neurocognitive deficit through a mechanism

other than the simple reversal of arterial hypoxia due to high levels of

COHb. The difficulty in accurately assessing neurocognitive deficit has

been one of the primary sources of controversy surrounding the clinical evidence in this area. To date, there have been six RCTs of HBO2

T

for CO poisoning, although only four have been reported in full. While

a Cochrane review suggested there is insufficient evidence to confirm a

beneficial effect of HBO2

T on the chance of persisting neurocognitive

deficit following poisoning (34% of patients treated with oxygen at 1

atmosphere vs 29%, of those treated with HBO2

T; odds ratio [OR],

0.78; 95% CI, 0.54–1.1), this may have more to do with poor reporting

and inadequate follow-up than with evidence that HBO2

T is not effective. The interpretation of the literature has much to do with how one

defines neurocognitive deficit. In the most methodologically rigorous

of these studies (Weaver et al.), a professionally administered battery

of validated neuropsychological tests and a definition based on the

deviation of individual subtest scores from the age-adjusted normal

values was used; if the patient complained of memory, attention, or

concentration difficulties, the required decrement was decreased.

Using this approach, 6 weeks after poisoning, 46% of patients treated

with normobaric oxygen alone had cognitive sequelae compared to

25% of those who received HBO2

T (p = .007; number needed to treat

[NNT] = 5; 95% CI, 3–16). At 12 months, the difference remained

significant (32 vs 18%; p = .04; NNT = 7; 95% CI, 4–124) despite considerable loss to follow-up.

On this basis, HBO2

T remains widely advocated for the routine

treatment of patients with moderate to severe poisoning—in particular in those older than 35 years, presenting with a metabolic acidosis

on arterial blood-gas analysis, exposed for lengthy periods, or with

a history of unconsciousness. Conversely, many toxicologists remain

unconvinced about the place of HBO2

T in this situation and call for

further well-designed studies.

CURRENT CONTROVERSIES IN

HYPERBARIC MEDICINE

The use of hyperbaric oxygen has been associated with controversy

since it was first instituted in the 1950s. A vigorous debate has recently

developed around the concept of performing sham controlled RCTs,

particularly when assessing outcomes where a placebo effect could significantly influence interpretation. The most popular method employed

to achieve blinding of both staff and patients is the exposure of patients

in the control arm to a modest pressure while breathing air in the chamber (between 1.1 and 1.3 ATA). While this strategy is effective in blinding the exposure, critics claim this exposure to air at pressure (equivalent

to breathing ~27% oxygen at 1.0 ATA) is therapeutic in a way yet to be

identified. These critics use this putative therapeutic effect to explain the

modest measured benefits in patients with a range of chronic neurologic

conditions including cerebral palsy, autism spectrum disorders, and

mild traumatic brain injury when exposed to either air at 1.1–1.3 ATA

or 100% oxygen at 2.0–2.4 ATA (HBO2

T) in a number of trials. These

benefits have traditionally been interpreted as the result of a participation or placebo effect, with the various authors concluding there was

no evidence of a specific effect for HBO2

T in any of these conditions.

The search continues for a convincing sham exposure that is universally

regarded as inactive. Some workers claim this is not possible and that

patient-blinded trials are therefore similarly unachievable. This impasse

needs resolution, and there is some hope that the restriction of pressure

exposure to short periods of modest compression at the start and end

of each sham session may be convincing for both sides of the argument.

DIVING MEDICINE

■ INTRODUCTION

Underwater diving is both a popular recreational activity and a means

of employment in a range of tasks from underwater construction to

military operations. It is a complex activity with unique hazards and

medical complications arising mainly as a consequence of the dramatic

changes in pressure associated with both descent and ascent through

the water column. For every 10.1-m increase in depth of seawater, the

ambient pressure (Pamb) increases by 101.3 kPa (1 atmosphere) so that,

for example, a diver at 20 m depth is exposed to a Pamb of 303.9 kPa

(3 ATA), made up of 1 ATA due to atmospheric pressure and 2 ATA

generated by the water column.

■ BREATHING EQUIPMENT

Most diving is undertaken using self-contained underwater breathing

apparatus (scuba) consisting of one or more cylinders of compressed

gas connected to a pressure-reducing regulator and a demand valve

activated by inspiratory effort. Some divers use “rebreathers,” which

comprise a closed or semi-closed breathing circuit with a carbon

dioxide scrubber and an oxygen addition system designed to maintain a safe inspired Po2

. Exhaled gas is recycled, and gas consumption

is limited to little more than the oxygen metabolized by the diver.

Rebreathers are therefore popular for deep dives where expensive

helium is included in the respired mix (see below). Occupational divers

frequently use “surface supply” equipment where gas, along with other

utilities such as communications and power, is supplied via an “umbilical”

cable from the surface.

All these systems must supply gas to the diver at the Pamb of the surrounding water or inspiration would be impossible against the water

pressure. For most recreational diving, the respired gas is air. Pure

oxygen is rarely used because there is a dose-dependent risk (where

“dose” is a function of exposure time and inspired Po2

) that oxygen

may provoke seizures above an inspired Po2

 of 130 kPa (1.3 ATA).

The maximum acceptable inspired Po2

 in diving is often considered to

be 161 kPa (1.6 ATA), which would be achieved when breathing pure

oxygen at 6 m or air at 66 m. This is a conspicuously lower Po2

 than

routinely used for hyperbaric therapy (see earlier), reflecting a higher

risk of oxygen toxic seizures during immersion and exercise. In order

to avoid dangerous oxygen exposures, very deep diving requires the

use of inspired oxygen fractions lower than in air (Fo2

 0.21), and divers

tailor the oxygen content of their gases to remain within recommended

exposure guidelines. Deep-diving gases include helium as a substitute

for some or all of the nitrogen to reduce both the narcotic effect and

high gas density that result from breathing nitrogen at high pressures.

■ SUITABILITY FOR DIVING

The most common reason for physician consultation in relation to diving is for the evaluation of suitability for diver training or continuation

of diving after a health event. Occupational diver candidates are usually

compelled to see doctors with specialist training in the field, both at

entry to the industry and periodically thereafter, and their medical evaluations are usually conducted according to legally mandated standards.

In contrast, in most jurisdictions, prospective recreational diver candidates simply complete a self-assessment medical questionnaire prior to

diver training. If there are no positive responses, the candidate proceeds

directly to training, but positive responses mandate the candidate see

a doctor for evaluation of the identified medical issue. Prospective divers will often present to their family medicine practitioner for this purpose. In the modern era, such consultations have evolved from a simple

proscriptive exercise of excluding those with potential contraindications

to an approach in which each case is considered on its own merits and

an individualized evaluation of risk is made. Such evaluations require

integration of diving physiology, the impact of associated medical

problems, and knowledge of the specific medical condition(s) of the

candidate. A detailed discussion is beyond the scope of this chapter, but

several important principles are outlined below.

There are three primary questions that should be answered in

relation to any medical condition reported by a prospective diver: (1)

Could the condition be exacerbated by diving? (2) Could the condition

make a diving medical problem more likely? (3) Could the condition

prevent the diver from meeting the functional requirements of diving?

As examples of positive answers to these questions (respectively):

epilepsy is usually considered to imply high risk because there are epileptogenic stimuli such as high inspired oxygen pressures encountered

in diving that could make a seizure (and drowning) more likely; active